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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects
Sulma I Mohammed1, Deepika Dhawan, Shaji Abraham
1Department of Veterinary Clinical Sciences, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026, USA.
Abstract:
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.
Insights
Cyclooxygenase (COX) inhibitors show promise against bladder cancer. Standard lab tests failed to predict effectiveness, but mouse models showed COX inhibitors delayed tumor growth, especially in COX-2 expressing tumors.
Area of Science:
- Oncology
- Pharmacology
Background:
- Transitional cell carcinoma (TCC) of the urinary bladder causes significant mortality.
- Cyclooxygenase (COX)-inhibiting drugs are being investigated for their potential antitumor effects in TCC.
- Optimal in vitro and in vivo models for studying COX inhibitor efficacy in TCC are not well-defined.
Purpose of the Study:
- To determine cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression in human TCC cell lines and xenografts.
- To evaluate the antitumor effects of COX inhibitors in these TCC models.
- To assess the utility of in vitro and in vivo systems for studying COX inhibitor effects in TCC.
Main Methods:
- Human TCC cell lines (HT1376, RT4, UMUC3) and their derived xenografts were used.
- COX-1 and COX-2 expression was analyzed using Western blot and immunocytochemistry.
- Antitumor effects of COX inhibitors (celecoxib, piroxicam, valeryl salicylate, NS398) were assessed in vitro proliferation assays and in vivo xenograft models in athymic mice.
Main Results:
- COX-2 expression varied across cell lines and xenografts, being high in HT1376, modest in RT4, and absent in UMUC3.
- In vitro, only high concentrations of celecoxib inhibited proliferation and induced apoptosis.
- In vivo, celecoxib and piroxicam significantly delayed the progression of HT1376 xenografts (COX-2 positive) but not UMUC3 xenografts (COX-2 negative).
Conclusions:
- Standard in vitro proliferation assays are inadequate for predicting the in vivo antitumor effects of COX inhibitors in TCC.
- Athymic mice bearing TCC xenografts represent a valuable in vivo system for studying COX inhibitors.
- Further investigation into COX inhibitors as potential antitumor agents for TCC is warranted.
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