Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11

Cancer Res. 2002 Oct 15;62(20):5778-84.

Abstract

Combining anticancer drugs with different mechanisms of action has the potential to enhance antitumor effect. CPT-11 (Camptosar, irinotecan), a topoisomerase I inhibitor, has been shown to be highly effective in the treatment of a variety of cancers. However, its clinical usage is often complicated by late diarrhea. A number of studies have shown that cyclooxygenase (COX)-2 is overexpressed in many forms of human tumors, suggesting that COX-2 inhibition may be useful in the treatment of cancer. In this study, we used two mouse tumor models (HT-29 and colon-26 cells) to evaluate the effect of combining CPT-11 with celecoxib on tumor growth. We also assessed the involvement of COX-2 in the pathogenesis of CPT-11-induced late diarrhea using a rat model. Results indicate that celecoxib enhances the antitumor effect of CPT-11 and reduces the severity of late diarrhea in a dose-dependent manner. The extended benefits of combining celecoxib with CPT-11 may significantly improve the outcome of cancer patients.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology*
  • Celecoxib
  • Colon / metabolism
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Diarrhea / chemically induced
  • Diarrhea / prevention & control*
  • Dinoprostone / biosynthesis
  • Dinoprostone / physiology
  • Drug Administration Schedule
  • Drug Synergism
  • HT29 Cells / drug effects
  • Humans
  • Irinotecan
  • Isoenzymes / antagonists & inhibitors*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Prostaglandin-Endoperoxide Synthases
  • Pyrazoles
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Weight Loss / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Pyrazoles
  • Sulfonamides
  • Irinotecan
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Celecoxib
  • Dinoprostone
  • Camptothecin