title: Effects of three modifiers of glycolysis on ATP, lactate, hypoxia, and growth in human tumor cell lines in vivo.
abstract: BACKGROUND
  High pretreatment tumor lactate content is associated with poor outcome after fractionated irradiation in human squamous cell carcinoma (hSCC) xenografts. Therefore, decreasing lactate content might be a promising approach for increasing tumor radiosensitivity. As the basis for such experiments, the effects of the biochemical inhibitors pyruvate dehydrogenase kinase dichloroacetate (DCA), lactate dehydrogenase oxamate, and monocarboxylic acid transporter-1 α-cyano-4-hydroxycinnamate (CHC) on tumor micromilieu and growth were investigated.
  
  
  METHODS
  Oxygen consumption (OCR) and extracellular acidification rates (ECAR) were measured in FaDu and UT-SCC-5 hSCC in response to DCA in vitro. Mice bearing FaDu, UT-SCC-5, and WiDr colorectal adenocarcinoma received either DCA in drinking water or DCA injected twice a day, or CHC injected daily. WiDr was also treated daily with oxamate. FaDu and UT-SCC-5 were either excised 8 days after treatment for histology or tumor growth was monitored. WiDr tumors were excised at 8 mm. Effect of inhibitors on ATP, lactate, hypoxia, and Ki67 labeling index (LI) was evaluated.
  
  
  RESULTS
  DCA increased OCR and decreased ECAR in vitro. None of the treatments with inhibitors significantly changed lactate content, hypoxia levels, and Ki67 LI in the three tumor lines in vivo. ATP concentration significantly decreased after only daily twice injections of DCA in FaDu accompanied by a significant increase in necrotic fraction. Tumor growth was not affected by any of the treatments.
  
  
  CONCLUSIONS
  Overall, tumor micromilieu and tumor growth could not be changed by glycolysis modifiers in the three tumor cell lines in vivo. Further studies are necessary to explore the impact of metabolic targets on radiation response.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Dept. of Radiation Oncology, Experimental Radiotherapy, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. ala.yaromina@tu-dresden.de
authors.forename: A
authors.initials: A
authors.lastname: Yaromina
authors.forename: S
authors.initials: S
authors.lastname: Meyer
authors.forename: C
authors.initials: C
authors.lastname: Fabian
authors.forename: K
authors.initials: K
authors.lastname: Zaleska
authors.forename: U G A
authors.initials: UG
authors.lastname: Sattler
authors.forename: L A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: W
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: D
authors.initials: D
authors.lastname: Zips
authors.forename: M
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D010072:Oxamic Acid / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: D003373:Coumaric Acids; D004791:Enzyme Inhibitors; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D010072:Oxamic Acid