title: Re-evaluation of cellular radiosensitization by 5-fluorouracil: high-dose, pulsed administration is effective and preferable to conventional low-dose, chronic administration.
abstract: OBJECTIVE
  It is widely believed that the anticancer drug 5- fluorouracil (5-FU) must be administered chronically and in low doses to maximize radiosensitization during chemoradiotherapy. The rationale is based upon cell experiments that assumed identical mechanisms of 5-FU action between low-dose chronic (LDC) and high-dose pulsed (HDP) exposures. Here we challenge the paradigm and demonstrate the effectiveness of HDP 5-FU as a radiosensitizer and the wide range of dose/time schedules that can be used to synergize with radiation as compared to the relatively restrictive protocols prescribed for current LDC administrations.
  
  
  METHODS
  Clonogenic survival of human glioblastoma and colon cancer cell lines, U87MG-VIII and HCT-116, respectively, was used to assess temporal and dose effects of 5-FU on radiosensitivity and in split-dose experiments to characterize changes in sublethal damage repair.
  
  
  RESULTS
  We show that HDP 5-FU administration does indeed radiosensitize both the highly radioresistant U87MG-VIII and HCT-116. Additionally, we show that this radiosensitization lasts for at least 24 h if cells are pre-irradiated with 2 Gy immediately after HDP 5-FU exposure as a result of a decrease in sublethal damage repair capacity for subsequent irradiations, suggesting the ideal combination of 5-FU bolus injection with fractionation radiotherapy schemes.
  
  
  CONCLUSIONS
  5-FU bolus administration protocols combined with radiation would not only help improve treatment outcomes and reduce development of 5-FU resistance, but it would greatly benefit patients by shortening clinical stays and lowering overall therapeutic costs.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at University of California , Los Angeles (UCLA), California , USA.
authors.forename: Gilmer
authors.initials: G
authors.lastname: Valdes
authors.forename: Keisuke S
authors.initials: KS
authors.lastname: Iwamoto
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology*; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D005472:Fluorouracil