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).

SUMMARY BACKGROUND DATA:

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: Tomoyuki Tanaka, Peter A Delong, Kunjlata Amin, Adam Henry, Robert Kruklitis, Veena Kapoor, Larry R Kaiser, Steven M Albelda
• Journal: Annals of surgery (Ann Surg) Vol. 241 Issue 1 Pg. 168-78 (Jan 2005) ISSN: 0003-4932 [Print] United States
• PMID: 15622005 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Lactones
• Sulfones
• rofecoxib

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• Cyclooxygenase Inhibitors (administration & dosage)
• Female
• Lactones (administration & dosage)
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Inbred BALB C
• Neoplasm Recurrence, Local (prevention & control)
• Pneumonectomy
• Sulfones (administration & dosage)
• Xenograft Model Antitumor Assays