5FU as a Prototype for the Design ofTargeted Therapy

This conference opened with Franco Muggia, host and principal organizer, thanking Joseph Landolph, co-Chair of the International Scientific Organizing Committee and its members (Franco Muggia, co-Chair, Max Costa, Steven Burakoff, Howard Hochster, Eliezer Huberman, John Bertram, Peter Danenberg, and Richard Moran); the members of the Local Organizing Committee (Drs. Costa, Guttenplan, Geacintov, and Hochster); and the Charles and Patricia Heidelberger Foundation for Cancer Research for developing the scientific program and for working to help him create this special symposium honoring the late Charles Heidelberger, former president of the American Association for Cancer Research, member of the National Academy of Sciences, and extraordinary scientist in the fields of carcinogenesis and cancer chemotherapy. It was most appropriate to commemorate the 50th anniversary of the patent obtained by him for 5-fluorouracil (5FU), a drug that came to symbolize the promise chemotherapy of nonhematologic malignancies. After this compound was shown to be helpful in the treatment of colorectal and breast cancers, Dr. Heidelberger proceeded to develop other fluoropyrimidines and to inspire Ph.D. students and postdoctoral fellows to investigate their mechanisms of action and to develop assays applicable to clinical specimens (what we now refer to as translational science). Steven Burakoff, director of the NYU Cancer Institute (2000 to 2008), followed with welcoming remarks. Dr. Burakoff pointed to his personal fortuitous connection to the Symposium: The famous immunologist, Michael Heidelberger, Charles’ father, who was known as the Father of Immunochemistry, trained Elvin Kabat while at Columbia, who trained Baruch Benacerraf, who moved from NYU to Harvard and subsequently became Burakoff’s mentor. The renowned NYU Division of Immunology carries the name Michael Heidelberger because he spent more than 30 years in the Department of Pathology at the NYU School of Medicine after retiring from Columbia University. [Mol Cancer Ther 2009;8(5):992–9] 5FU as a Prototype for the Design ofTargeted Therapy Targeted therapy has become the ideal of therapy in general and of cancer therapy in particular. From this perspective, 5FU and methotrexate (MTX) can be considered as the first rationally designed targeted anticancer drugs. Furthermore, the development of 5FU emerges as a prototype of translational research, not only in the last two decades when such research has been emphasized but, thanks to Heidelberger, even in the first few years after its discovery and introduction into the clinic. 5FU was developed on the basis of findings in the 1950s that cancer cells incorporated a larger amount of the uracil base into the DNA than normal cells (1, 2). From the halogensubstituted uracils, 5FU appeared to be the most active and promising drug (3), and clinical studies were immediately initiated (4), in which not only plasma concentrations were measured but also tissues’ disposition using radioactive 5FU (5). It was rapidly recognized that 5FU was metabolized by enzymes from normal pyrimidine metabolism (6) and that it was incorporated both into RNA and DNA (5), although it has long been debated what accounted for its antitumor effects. Also degradation pathways of 5FU were similar to the natural bases (7), demonstrating an important role for dihydropyrimidine dehydrogenase (DPD). 5FU can be activated by the subsequent action of uridine Received 8/4/08; revised 11/20/08; accepted 12/9/08; published OnlineFirst 5/5/09. Grant support: Supported in part by Cancer Center Core Grant CA16087; Chemotherapy Foundation & Heidelberger Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Franco M. Muggia, NYU Langone Medical Center, 550 First Avenue, BCD556, New York, NY 10016. Phone: 212-2636485; Fax: 212-263-8210. E-mail: [email protected] Copyright C 2009 American Association for Cancer Research. doi:10.1158/1535-7163.MCT-08-0731 Heidelberger Symposium: Meeting Report 992 Mol Cancer Ther 2009;8(5). May 2009 on April 20, 2017. © 2009 American Association for Cancer Research. mct.aacrjournals.org Downloaded from Published OnlineFirst May 5, 2009; DOI: 10.1158/1535-7163.MCT-08-0731