title: Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery.
abstract: OBJECTIVE
  To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non-small-cell lung cancer (NSCLC).
  
  
  BACKGROUND
  Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied.
  
  
  METHODS
  Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14-18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored.
  
  
  RESULTS
  Rofecoxib significantly slowed the growth of small (0-120 mm) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8 T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01).
  
  
  CONCLUSIONS
  Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC.
authors.affiliation: Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Peter A
authors.initials: PA
authors.lastname: Delong
authors.forename: Kunjlata
authors.initials: K
authors.lastname: Amin
authors.forename: Adam
authors.initials: A
authors.lastname: Henry
authors.forename: Robert
authors.initials: R
authors.lastname: Kruklitis
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Larry R
authors.initials: LR
authors.lastname: Kaiser
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D005260:Female; D007783:Lactones / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D011013:Pneumonectomy; D013450:Sulfones / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib