title: Short-term exposure of cancer cells to micromolar doses of paclitaxel, with or without hyperthermia, induces long-term inhibition of cell proliferation and cell death in vitro.
abstract: BACKGROUND
  During intraoperative hyperthermic intraperitoneal chemotherapy for primary or secondary peritoneal malignancies, tumor cells are exposed to high drug concentrations for a relatively short period of time. We investigated in vitro the effect of paclitaxel and hyperthermia on cell proliferation, cell cycle kinetics and cell death under conditions resembling those during intraoperative hyperthermic intraperitoneal chemotherapy.
  
  
  METHODS
  Human breast MCF-7, ovarian SKOV-3 and hepatocarcinoma HEpG2 cells were exposed to 10 and 20 microM paclitaxel at 37, 41.5 or 43 degrees C for 2 h. Cell proliferation, cell cycle kinetics, necrosis and apoptosis were evaluated.
  
  
  RESULTS
  Hyperthermia exerted a cytostatic effect to all cell lines and at 43 degrees C a cytotoxic effect on MCF-7 cells. MCF-7 and SKOV-3 cells treated under normothermic conditions with paclitaxel were arrested at G2/M or M phase for at least 3 days. Most of MCF-7 cells and approximately half of SKOV-3 cells were in interphase and became multinucleated without properly completing cytokinesis. Hyperthermia at 41.5 degrees C altered cell cycle distribution and affected the paclitaxel-related effect on cell cycle kinetics of MCF-7 and SKOV-3 cells. Analysis of the mode of cell death showed that cell necrosis prevailed over apoptosis. Hyperthermia at 43 degrees C increased paclitaxel-mediated cytotoxicity in MCF-7 cells and to a lesser extent in SKOV-3 and HEpG2 cells.
  
  
  CONCLUSIONS
  Short-time treatment of carcinoma cells with high (micromolar) concentrations of paclitaxel in normothermic and hyperthermic conditions is highly efficient for cell growth arrest and could be of clinical relevance in locoregional chemotherapy.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Crete, P.O. Box 2208, 71003, Heraklion, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Michalakis
authors.forename: Spyros D
authors.initials: SD
authors.lastname: Georgatos
authors.forename: Eelco
authors.initials: E
authors.lastname: de Bree
authors.forename: Hara
authors.initials: H
authors.lastname: Polioudaki
authors.forename: John
authors.initials: J
authors.lastname: Romanos
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
authors.forename: Dimitris D
authors.initials: DD
authors.lastname: Tsiftsis
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Theodoropoulos
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000628:therapy; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005334:Fever; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000628:therapy; D009336:Necrosis; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel