title: The range of optimal concentration and mechanisms of paclitaxel in radio-enhancement in gastrointestinal cancer cell lines.
abstract: OBJECTIVE
  This study was performed to investigate the range of optimal concentration and mechanisms of paclitaxel (PXL) radio-enhancement in gastrointestinal cancer cell lines HT29 and MKN45.
  
  
  METHODS
  Cell growth inhibition by PXL pretreatment at various concentrations (0-10 microM) followed by irradiation was investigated using a modified MTT assay. To investigate the mechanisms of the observed radio-enhancement, flow cytometry was conducted to define the cell cycle distributions. Furthermore, the alterations in expression of a DNA repair molecule [excision repair cross-complementation group1 (ERCC1)] and an angiogenesis factor [vascular endothelial growth factor (VEGF)] induced by PXL were investigated.
  
  
  RESULTS
  Cytotoxic concentrations of PXL (0.1-10 microM) that cause accumulation of cells in the G2/M phase have strong radio-enhancing effects and inhibit total cell growth. The maximal non-cytotoxic concentration of PXL (0.01 microM) also had a radio-enhancing effect. The expression of the genes of ERCC1 and VEGF induced by radiation was suppressed by PXL pretreatment. The protein secretion of VEGF induced by radiation was suppressed at cytotoxic doses of PXL, and the induced protein secretion of ERCC1 was also suppressed even at maximal non-cytotoxic doses of PXL.
  
  
  CONCLUSIONS
  The range of optimal concentration for PXL pretreatment was 0.01-0.1 microM in these cells. Two major mechanisms of radio-enhancement are suggested: (1) PXL induces G2/M arrest leading to increased DNA damage after radiation, which results in mitotic death, and (2) PXL suppresses the expression of radiation-induced DNA repair molecules and angiogenesis factors, resulting in inhibition of cell growth and cell death.
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiro
authors.forename: Eiki
authors.initials: E
authors.lastname: Ojima
authors.forename: Hideki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Youhei
authors.initials: Y
authors.lastname: Narita
authors.forename: Atuko
authors.initials: A
authors.lastname: Hosono
authors.forename: Chikao
authors.initials: C
authors.lastname: Miki
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D019073:HT29 Cells; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011829:Radiation Dosage; D011838:Radiation-Sensitizing Agents; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel