XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on September 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center

Abstract

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.

DNA mismatch repair proficiency executing 5-fluorouracil cytotoxicity in colorectal cancer cells

“…On the other hand, our data also suggests the importance of the futile cycle model which for patients simulate long-term or sustained 5-FU treatment over time, compared with the direct damage model which may simulate a single treatment of 5-FU. 33 A single dose treatment allows for a rapid recovery of the dTTP pool, and any 5FdU-containing sites within DNA cannot remain for long periods due to subsequent repair with dTTPs. In this scenario, the opportunity for DNA MMR to trigger the majority of cancer cells to undergo cell death may be low.…”

Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2′-deoxy-5-fluorouridine into DNA

“…Thus, the pyrimidine synthesis pathway involving deoxythymidine (dThd; Fig. 1 ) biosynthesis was recognized in early studies as a target for solid tumor chemotherapy with drugs, such as 5-fluorouracil (5-FU) and/or antifolate agents ( 3 , 4 ).…”

Multicellular Spheroid Culture Models: Applications in prostate Cancer Research and Therapeutics

“…High PARP expression in prostate cancer cell lines compared to benign cell lines has already been reported, in which greater than 90% of LNCaP cells showed positivity for PARP before and after treatment with H2O2 [54]. In LNCaP spheroids, expression of PARP-1 was detected and confined to the intermediate zone ( Figure 2a) [37,45], but real-time PCR demonstrated that expression of PARP-1 in 2D cultures is higher than in spheroid cultures. The specific location means that PARP maycontribute to the characteristics of the quiescent cells within the LNCaP spheroids, being linked with the target molecule in prostate cancer treatments.…”

“…MCS of LNCaP cells exhibit disordered but tight cell-cell contacts, and their characteristics differ according to the location [13]. In two studies, the tumor cells of the intermediate zone were found to be positive for p27 and poly (ADP-ribose) polymerase 1 (PARP-1), but negative for Ki-67 ( Figure 2a) [13,45]. These cells thus appear to be quiescent.…”