title: Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells.
abstract: 5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2'-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2'-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2'-deoxyuridine and, to a lesser extent, 5-hydroxy-2'-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2'-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies.
authors.affiliation: Department of Internal Medicine and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA ; Howard Hughes Medical Institute Student Scientist, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA ; Department of Communication Sciences and Disorders, Temple University, Philadelphia, Pennsylvania.
authors.forename: Victoria
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Department of Biological Sciences, East Stroudsburg University, East Stroudsburg, Pennsylvania, USA.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Whitford
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA ; LAM Therapeutics, Guilford, Connecticut.
authors.forename: Neil
authors.initials: N
authors.lastname: Beeharry
authors.affiliation: Department of Mathematical and Life Sciences, Hiroshima University, Higashi-Hiroshima JAPAN.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ide
authors.affiliation: Department of Internal Medicine and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Tomkinson
keywords: 5-Fluorouracil; Cytotoxicity; Deoxyuridine Analog; Synergy