title: Concentration-dependent radiosensitizing effect of docetaxel in esophageal squamous cell carcinoma cells.
abstract: Taxanes, paclitaxel and docetaxel (DTX) are anticancer agents that exhibit cytotoxicity by inhibiting microtubule polymerization. They enhance the radiosensitivity of various cancers by blocking the cell cycle in the most radiosensitive G2/M phase. Recently, taxanes have been reported to have different mechanisms of action depending on dose intensity. However, the mechanism of the radio-enhancing effect of DTX in relation to the drug dose intensity is not clearly understood. In the present study, we experimentally investigated the radio-enhancing effects of various concentrations of DTX against esophageal squamous cell cancer (ESCC); KES cells were used for in vitro confirmation of the effective administration schedule for DTX in chemoradiotherapy involving ESCC. DTX enhanced radiation cell killing in a concentration-dependent manner in KES cells. High cytotoxic concentrations (>10 nM) of DTX strongly enhanced radiosensitivity. Low concentrations (<1 nM) of DTX that did not have a cytotoxic effect showed a radio-enhancing effect by inducing DNA double strand breaks and apoptosis after irradiation. Low and high concentrations of DTX induced radiosensitive G0/G1 and G2/M phase arrest, respectively in KES cells. Cells treated with high concentrations of DTX exhibited nuclear aggregation associated with apoptotic change. In contrast, cells treated with low concentrations of DTX displayed multi-nucleation or unequal division. In conclusion, enhancement of the radiosensitivity of ESCC cells by DTX was demonstrated, even using nanomolar concentrations that did not have a cytotoxic effect. DTX has different radio-enhancing mechanisms depending on its concentration. Therefore, weekly administration of DTX might effectively enhance radiation cytotoxicity in the treatment of ESCC.
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Miyanaga
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsukada
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Center for Biomedical Research and Education, School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakanuma
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Seisho
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Makino
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Nakagawara
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel