title: Ethynyldeoxyuridine (EdU) suppresses in vitro population expansion and in vivo tumor progression of human glioblastoma cells.
abstract: Thymidine analogs (TAs) are synthetic nucleosides that incorporate into newly synthesized DNA. Halogenated pyrimidines (HPs), such as bromodeoxyuridine (BrdU), are a class of TAs that can be detected with antibodies and are commonly used for birthdating individual cells and for assessing the proliferative index of cell populations. It is well established that HPs can act as radiosensitizers when incorporated into DNA chains, but they are generally believed not to impair normal cell function in the absence of secondary stressors. However, we and others have shown that HP incorporation leads to a sustained suppression of cell cycle progression in mammalian cells, resulting in cellular senescence in somatic cells. In addition, we have shown that HP incorporation results in delayed tumor progression in a syngeneic rat model of glioma. Here we examine ethynyldeoxyuridine (EdU), a newly developed and alkylated TA, for its anti-cancer activity, both in vitro and in vivo. We show that EdU, like HPs, leads to a severe reduction in the proliferation rate of normal and transformed cells in vitro. Unlike HPs, however, EdU incorporation also causes DNA damage resulting in the death of a substantial subset of treated cells. When administered over an extended time as a monotherapy to mice bearing subcutaneous xenografts of human glioblastoma multiforme tumors, EdU significantly reduces tumor volume and increases survival without apparent significant toxicity. These results, combined with the fact that EdU readily crosses the blood-brain barrier, support the continued investigation of EdU as a potential therapy for malignant brain tumors.
authors.affiliation: Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Ross
authors.forename: Maryam
authors.initials: M
authors.lastname: Rahman
authors.forename: Lindsay H
authors.initials: LH
authors.lastname: Levkoff
authors.forename: Sebastien
authors.initials: S
authors.lastname: Millette
authors.forename: Teresa
authors.initials: T
authors.lastname: Martin-Carreras
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dunbar
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
authors.forename: Eric D
authors.initials: ED
authors.lastname: Laywell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D013936:Thymidine / Q000031:analogs & derivatives*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013936:Thymidine