The third Paul Ehrlich lecture basic research as forerunner of new medications
1991; Wiley; Volume: 11; Issue: 1 Linguagem: Inglês
10.1002/med.2610110102
ISSN1098-1128
Autores Tópico(s)Historical Medical Research and Treatments
ResumoMedicinal Research ReviewsVolume 11, Issue 1 p. 1-15 Article The third Paul Ehrlich lecture† basic research as forerunner of new medications George H. Hitchings, George H. Hitchings Wellcome Research Laboratories, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, North Carolina 27709 George H. Hitchings: began life in the Pacific Northwest. His elementary schooling was in Berkley and San Diego, California, and in Bellingham and Seattle, Washington. He grew up in Seattle, was graduated from Franklin High School, and took his BS. and MS. at the University of Washington (1927, 1928). His Ph.D. was earned at Harvard Medical School in 1933. He had begun university with a medical career in mind. This goal probably was initiated by the early death of his father when he was 12 years old. It had its first expression in his Salutatory address at high school graduation. That was based on the life of Louis Pasteur, who became a role model of scientific excellence combined with service to mankind. Hitchings entered the University of Washington with a premedical course in mind but became enchanted with chemistry. His eventual Ph.D. in biochemistry was a synthesis of two goals. His doctorate came at the nadir of the great depression. His thesis and reading had made him an enthusiast for nucleic acid chemistry and biochemistry. It was 9 years of other types of employment before the opportunity to develop these interests was available. He joined Burroughs Wellcome Co. (a pharmaceutical house notable for basic research and owned ultimately by the philanthropic Wellcome Trust) in July, 1942. Sulfanilamide and the antimetabolite principle were new, and Hitchings saw the chance to exploit his interest in nucleic acids by applying the concept of antimetabolic activity to the biosynthesis of DNA and RNA. He enlisted the help of Elvira Falco and the Lactobacillus casei test was developed. This was the foundation of the goals of the department for many years. The test revealed, with 10–15 mg of compound, whether a compound was adeninelike, thyminelike, folic-acid-like, or an antagonist of one of these nucleicacid constituents. Hitchings's department gradually grew. Gertrude Elion (who shared the Nobel Prize in 1988) joined in 1944; Peter Russell, Norman Whittaker, the Biebers, and others also joined, so that by 1947 there were 7 or 8 in the group. Exciting chemotherapeutic activity was just in the offing. A spectacular remission of acute leukemia in 1948 was accompanied by exciting antibacterial results, especially with diaminopyrimidines (acting as antifolics). The development of 6-mercaptopurine (6-MP) as an antileukemic became dramatic. In 1954, the New York Academy of Sciences held a two-day symposium on it with 83 participants, 41 papers, and 324 pages in the Annals of the New York Academy of Sciences. The discovery by Schwartz and Dameshek that (6-MP) was immunosuppressive led eventually to successful kidney transplantation in dogs by Calne and Murray, and to Murray's first successful renal transplant in man where donor and recipient differed genetically. Allopurinol, an inhibitor of xanthine oxidase, was waiting in the wings. Its efficacy in vivo was first established by its inhibitory effect on the catabolism of mercaptopurine in animals and in man, but soon led logically to a treatment for gout and hyperuricemia (pioneered by R. Wayne Rundles). This has been a unique major medication for some 30 years. Meanwhile, work on the diaminopyrimidines (led by Falco) resulted in a highly active, highly selective inhibitor of dihydrofolate reductase (trimethoprim). This inhibitor, logically combined with a sulfonamide, produced co-trimoxazole, credited with saving about one million lives from bacterial and protozoal infections. Early work with Randall Thompson led to an antivaccinial compound probably active against smallpox. (The disease was eliminated from the world a few years later.) Antiviral work was never totally put aside—it became a major activity about 1970, when acyclovir (an antiherpetic compound) was developed (led by Gertrude Elion). Zydovudine (an anti-AIDS compound) was soon developed by David Barry. Both compounds fit the original program, using nucleic acid biosynthesis as targets. The work of the Hitchings's group has been recognized by numerous awards, culminating in the Nobel Prize for 1988, and the Schweitzer Award in 1989.Search for more papers by this author George H. Hitchings, George H. Hitchings Wellcome Research Laboratories, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, North Carolina 27709 George H. Hitchings: began life in the Pacific Northwest. His elementary schooling was in Berkley and San Diego, California, and in Bellingham and Seattle, Washington. He grew up in Seattle, was graduated from Franklin High School, and took his BS. and MS. at the University of Washington (1927, 1928). His Ph.D. was earned at Harvard Medical School in 1933. He had begun university with a medical career in mind. This goal probably was initiated by the early death of his father when he was 12 years old. It had its first expression in his Salutatory address at high school graduation. That was based on the life of Louis Pasteur, who became a role model of scientific excellence combined with service to mankind. Hitchings entered the University of Washington with a premedical course in mind but became enchanted with chemistry. His eventual Ph.D. in biochemistry was a synthesis of two goals. His doctorate came at the nadir of the great depression. His thesis and reading had made him an enthusiast for nucleic acid chemistry and biochemistry. It was 9 years of other types of employment before the opportunity to develop these interests was available. He joined Burroughs Wellcome Co. (a pharmaceutical house notable for basic research and owned ultimately by the philanthropic Wellcome Trust) in July, 1942. Sulfanilamide and the antimetabolite principle were new, and Hitchings saw the chance to exploit his interest in nucleic acids by applying the concept of antimetabolic activity to the biosynthesis of DNA and RNA. He enlisted the help of Elvira Falco and the Lactobacillus casei test was developed. This was the foundation of the goals of the department for many years. The test revealed, with 10–15 mg of compound, whether a compound was adeninelike, thyminelike, folic-acid-like, or an antagonist of one of these nucleicacid constituents. Hitchings's department gradually grew. Gertrude Elion (who shared the Nobel Prize in 1988) joined in 1944; Peter Russell, Norman Whittaker, the Biebers, and others also joined, so that by 1947 there were 7 or 8 in the group. Exciting chemotherapeutic activity was just in the offing. A spectacular remission of acute leukemia in 1948 was accompanied by exciting antibacterial results, especially with diaminopyrimidines (acting as antifolics). The development of 6-mercaptopurine (6-MP) as an antileukemic became dramatic. In 1954, the New York Academy of Sciences held a two-day symposium on it with 83 participants, 41 papers, and 324 pages in the Annals of the New York Academy of Sciences. The discovery by Schwartz and Dameshek that (6-MP) was immunosuppressive led eventually to successful kidney transplantation in dogs by Calne and Murray, and to Murray's first successful renal transplant in man where donor and recipient differed genetically. Allopurinol, an inhibitor of xanthine oxidase, was waiting in the wings. Its efficacy in vivo was first established by its inhibitory effect on the catabolism of mercaptopurine in animals and in man, but soon led logically to a treatment for gout and hyperuricemia (pioneered by R. Wayne Rundles). This has been a unique major medication for some 30 years. Meanwhile, work on the diaminopyrimidines (led by Falco) resulted in a highly active, highly selective inhibitor of dihydrofolate reductase (trimethoprim). This inhibitor, logically combined with a sulfonamide, produced co-trimoxazole, credited with saving about one million lives from bacterial and protozoal infections. Early work with Randall Thompson led to an antivaccinial compound probably active against smallpox. (The disease was eliminated from the world a few years later.) Antiviral work was never totally put aside—it became a major activity about 1970, when acyclovir (an antiherpetic compound) was developed (led by Gertrude Elion). Zydovudine (an anti-AIDS compound) was soon developed by David Barry. Both compounds fit the original program, using nucleic acid biosynthesis as targets. The work of the Hitchings's group has been recognized by numerous awards, culminating in the Nobel Prize for 1988, and the Schweitzer Award in 1989.Search for more papers by this author First published: January 1991 https://doi.org/10.1002/med.2610110102Citations: 3 † Presented by Dr. George H. Hitchings on April 26, 1990, at the National Institutes of Health, Bethesda, MD. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume11, Issue1January 1991Pages 1-15 RelatedInformation
Referência(s)