title: Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma.
abstract: Sarcomas are relatively resistant because of hypoxia. We previously demonstrated that the transcutaneous CO(2) therapy reduced hypoxic conditions in human malignant fibrous histiocytoma (MFH). Therefore, we hypothesized that transcutaneous CO(2) therapy could enhance the antitumor effect of radiation therapy in human MFH. Our purpose was to evaluate the effects of transcutaneous CO(2) therapy on the antitumor efficacy of X-ray irradiation using MFH. First, in an in vitro study, we assessed apoptotic activity and reactive oxygen species (ROS) production using flow cytometric and immunoblot analysis at 24 h after X-ray irradiation under three different oxygen conditions (normoxic, reoxygenated and hypoxic). In addition, in the in vivo study, 24 male athymic BALB/c nude mice with MFH tumors that were inoculated in the dorsal subcutaneous area were randomized into four groups: control, CO(2), X-ray irradiation and combination (CO(2) and X-ray irradiation). Treatments were performed twice weekly for 2 weeks, four times in total. Tumor volume was calculated. All tumors were excised and apoptotic activity, ROS production, related proteins and HIF-1α expression were assessed using flow cytometric and immunoblot analysis. The in vitro study revealed that X-ray irradiation induced increased apoptosis and ROS production in MFH cells under normoxic and reoxygenated conditions relative to hypoxic conditions (P<0.01). In the in vivo study, tumor volume in the combination group was reduced to 28, 42 and 47% of that in the control, CO(2), and X-ray groups, respectively (P<0.05). Apoptotic activity and ROS production in the combination group were strongly increased with decreasing HIF-1α expression relative to the control, CO(2) and X-ray groups. The transcutaneous CO(2) system enhanced the antitumor action of X-ray irradiation and could be a novel therapeutic tool for overcoming radio-resistance in human malignancies.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akisue
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Teruya
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: NeoChemir Inc., Sannomiya Chuo-Building 4F, Chuo-ku, Kobe 651-0087, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueha
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Harada
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Minoda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Morishita
authors.affiliation: Department of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sasaki
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D051677:Histiocytoma, Malignant Fibrous / Q000628:therapy*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011878:Radiotherapy / Q000379:methods*; D017382:Reactive Oxygen Species; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D002245:Carbon Dioxide