The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases.

Abstract

BACKGROUND & AIMS:

Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial.

METHODS:

Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (AI; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated.

RESULTS:

Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in AI (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (>10 micromol/L), which were significantly higher than the IC(50) for COX-2 inhibition.

CONCLUSIONS:

Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.

• Authors: Stephen W Fenwick, Giles J Toogood, J Peter A Lodge, Mark A Hull
• Journal: Gastroenterology (Gastroenterology) Vol. 125 Issue 3 Pg. 716-29 (Sep 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12949718 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Lactones
• Membrane Proteins
• Sulfones
• rofecoxib
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Aged
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Colorectal Neoplasms (blood supply, drug therapy)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (therapeutic use)
• Dinoprostone (biosynthesis)
• Double-Blind Method
• Female
• Humans
• Isoenzymes (antagonists & inhibitors)
• Lactones (therapeutic use)
• Liver Neoplasms (blood supply, secondary)
• Male
• Membrane Proteins
• Middle Aged
• Prostaglandin-Endoperoxide Synthases
• Sulfones