Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer

J Gastrointest Surg. Nov-Dec 2002;6(6):838-43; discussion 844. doi: 10.1016/s1091-255x(02)00061-6.

Abstract

Recent studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer. A human pancreatic adenocarcinoma cell line, Mia PaCa-2, was incubated for 18 hours with 5 micromol/L of rofecoxib (Vioxx), a selective COX-2 inhibitor. Total RNA was isolated and gene expression analyzed by DNA microarray chips. In a separate experiment, athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy. After 1 month, laparotomy was repeated to measure tumor size, and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days. Tumor growth was assessed by comparing volume before and after treatment. In vitro, rofecoxib decreased gene expression of cyclin D1/PRAD1, a key component of cell cycle progression, while increasing expression of several cell cycle arrest genes, including p21/WAF1, p33/ING, GADD34, and GADD45 (P < 0.05). In vivo, tumor growth was significantly reduced in treated vs. control mice (P < 0.05). No systemic toxicity was observed in mice receiving rofecoxib. These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Cycle / drug effects*
  • Cell Cycle / genetics*
  • Cyclin D1 / genetics
  • Cyclooxygenase Inhibitors / pharmacology
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lactones / pharmacology*
  • Lactones / toxicity
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pancreas / drug effects
  • Pancreas / pathology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Probability
  • Random Allocation
  • Reference Values
  • Sensitivity and Specificity
  • Sulfones
  • Tumor Cells, Cultured / drug effects

Substances

  • Cyclooxygenase Inhibitors
  • Lactones
  • Sulfones
  • rofecoxib
  • Cyclin D1