title: Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa(TM)) and to the antiangiogenic agent ZD6474: Cytotoxic and biomolecular effects.
abstract: OBJECTIVE
  To analyze the biological effects of prolonged in vitro exposure of HT-29 and LoVo colon cancer cell lines to gefitinib (Iressa), an inhibitor of epidermal growth factor receptor (EGFR) activity, and ZD6474, an inhibitor of both KDR and EGFR activities.
  
  
  METHODS
  Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent (4 d of drug exposure followed by 3 d of washout each week) schedule.
  
  
  RESULTS
  In both cell types, prolonged exposure (up to 14 d) to gefitinib or ZD6474 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule. The effects on cell growth were associated with a pronounced inhibition of p-EGFR and/or p-KDR expression. Treatment with gefitinib or ZD6474 also inhibited the expression of EGFR downstream signal molecules, p-Erk1/2 and p-Akt, although the magnitude of these effects varied between treatments and cell lines. Furthermore, expression of the drug resistance-related protein ABCG2 was shown to significantly increase after 14 d of continuous exposure to the two drugs.
  
  
  CONCLUSIONS
  We conclude that long-term exposure of colon cancer cells to gefitinib and ZD6474 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Xu
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Simone
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib; C452423:vandetanib