title: Combination of Photon and Carbon Ion Irradiation with Targeted Therapy Substances Temsirolimus and Gemcitabine in Hepatocellular Carcinoma Cell Lines.
abstract: BACKGROUND
  This work investigates on putative cytotoxic effects in four different hepatocellular carcinoma (HCC) cell lines after irradiation with photons or carbon ions in combination with new targeted molecular therapy using either Temsirolimus (TEM) or Gemcitabine (GEM).
  
  
  METHODS
  The HCC cell lines HepG2, Hep3B, HuH7, and PLC were cultured and irradiated with photons or carbon ions at the Heidelberg Ion Beam Therapy Center using the raster-scanning method. For combination experiments, cell lines were first treated with Temsirolimus or GEM before irradiation. Cytotoxicity was measured by a clonogenic survival assay. The evaluation of the experiments and the obtained survival curves were based on the concept of additivity defined by Steel and Peckham.
  
  
  RESULTS
  The results for the combination of carbon ions and both tested systemic substances TEM and GEM showed independent toxicities in all four cell lines. Supra-additive effects were observed in PLC cells for photon irradiation combined either with TEM or GEM and in HuH7 cells for the combination of photons with TEM.
  
  
  CONCLUSIONS
  Addition of targeted therapy substances Temsirolimus and GEM to photon irradiation showed additive cytotoxicity in HCC cell lines, whereas independent toxicities where reached by the combination of carbon ions to these substances. It can be assumed that combining 12C with systemic substances only has independent effects because heavy ions cause direct damage because of their high-LET character resulting in complex and clustered double-strand breaks. Nonetheless, further investigations are warranted in order to determine whether addition of systemic therapy allows a reduction of radiation doses in combination therapy. This could possibly lead to better responses and tolerances in patients with HCC.
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dehne
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Fritz
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rieken
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Baris
authors.affiliation: Heidelberg Ion Beam Therapy Center (HIT) , Heidelberg , Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brons
authors.affiliation: Heidelberg Ion Beam Therapy Center (HIT) , Heidelberg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haberer
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg , Heidelberg , Germany.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich , Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Schmid
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich , Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich , Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Habermehl
keywords: Gemcitabine; Temsirolimus; carbon ion irradiation; combined modality treatment; hepatocellular carcinoma