Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects.
More than 14,000 people die from invasive transitional cell carcinoma (TCC) of the urinary bladder yearly in the United States. Cyclooxygenase (COX)-inhibiting drugs are emerging as potential antitumor agents in TCC. The optimal in vitro or in vivo systems to investigate COX inhibitor antitumor effects have not been defined. The purpose of this study was to determine COX-1 and COX-2 expression and antitumor effects of COX inhibitors in human TCC cell lines (HT1376, RT4, and UMUC3 cells) and xenografts derived from those cell lines. COX-2 expression (Western blot, immunocytochemistry) was high in HT1376, modest in RT4, and absent in UMUC3 cells in vitro. Similarly, COX-2 expression was noted in RT4 but not UMUC3 xenografts. COX-2 expression in HT1376 xenografts was slightly lower than that observed in vitro. None of four COX inhibitors evaluated (celecoxib, piroxicam, valeryl salicylate, and NS398) reduced TCC growth in standard in vitro proliferation assays at concentrations that could be safely achieved in vivo (< or =5 micromol/L). Higher celecoxib concentrations (> or =50 micromol/L) inhibited proliferation and induced apoptosis in all three cell lines. Celecoxib or piroxicam treatment in athymic mice significantly delayed progression of HT1376 xenografts, which express COX-2, but not UMUC3 xenografts that lack COX-2 expression. In conclusion, standard in vitro assays were not useful in predicting COX inhibitor antitumor effects observed in vivo. Athymic mice bearing TCC xenografts provide a useful in vivo system for COX inhibitor studies. Results of this study provide justification for further evaluation of COX inhibitors as antitumor agents against TCC.
Mohammed
Sulma I
SI
Department of Veterinary Clinical Sciences, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026, USA.
Dhawan
Deepika
D
Abraham
Shaji
S
Snyder
Paul W
PW
Waters
David J
DJ
Craig
Bruce A
BA
Lu
Ming
M
Wu
Lan
L
Zheng
Rong
R
Stewart
Jane
J
Knapp
Deborah W
DW
D000818:Animals; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human