title: S-phase-specific radiosensitization by gemcitabine for therapeutic carbon ion exposure in vitro.
abstract: Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays-increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ∼70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms-,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase-specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically.
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany Heidelberg Ion Therapy Center (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany semi.harrabi@med.uni-heidelberg.de.
authors.forename: Semi B
authors.initials: SB
authors.lastname: Harrabi
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Adeberg
authors.affiliation: Heidelberg Ion Therapy Center (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Winter
authors.affiliation: Heidelberg Ion Therapy Center (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haberer
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany Heidelberg Ion Therapy Center (HIT), Im Neuenheimer Feld 450, Heidelberg 69120, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D063193:Heavy Ion Radiotherapy; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects* / Q000528:radiation effects*; D016196:S Phase / Q000187:drug effects* / Q000528:radiation effects*; D014410:Tumor Stem Cell Assay; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: S-phase; carbon ion irradiation; gemcitabine; radiosensitization