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Updated: Jul 12, 2026
An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Efficacy of EGFR Inhibitors and NSAIDs Against Basal Bladder Cancers in a Rat Model: Daily vs. Weekly Dosing,
Ronald A Lubet1, Amit Kumar2, Jennifer T Fox1
1Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Background:
There are few effective treatments specifically aimed at basal bladder cancer.
Objective:
Female F344 rats administered N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) develop large invasive bladder cancers. We determined the efficacy of daily vs weekly dosing of EGFR inhibitors, determined the efficacy of naproxen combined with an EGFR inhibitor, and performed RNA analysis of bladder tumors treated for 5 days with EGFR inhibitors or NO-naproxen to identify pharmacodynamic biomarkers.
Methods:
Erlotinib (6 mg/Kg BW daily or 21 or 42 mg/Kg BW weekly), lapatinib (25 or 75 mg/Kg BW daily or 263 or 525 mg/Kg BW weekly) and/or naproxen (30 mg/Kg BW daily) were administered to OH-BBN-treated rats beginning 2-12 weeks post OH-BBN. Rats were sacrificed 28 weeks after the final OH-BBN treatment to determine the effects of the EGFR inhibitors + naproxen on bladder weights and tumor development. In a separate study, rats were treated with OH-BBN. When palpable tumors developed, rats were treated with erlotinib, lapatinib, gefitinib, or the NSAID NO-naproxen for 5 days. RNA analysis was performed on the tumors.
Results:
Daily or weekly dosing of erlotinib or lapatinib and daily dosing of naproxen reduced large tumor formation up to 70%, while combining daily lapatinib and naproxen reduced tumors 100%. RNA Analysis: All EGFR inhibitors strongly reduced cell proliferation and chromosome replication pathways, while NO-naproxen altered the G protein receptor, oxygen homeostasis and immune function pathways.
Conclusions:
While daily and weekly dosing with EGFR inhibitors and naproxen were effective, combining lapatinib and naproxen yielded no tumors. This might encourage its clinical use in an adjuvant setting with superficial basal tumors, and perhaps even in a more advanced setting. Furthermore, RNA analysis identified specific pathways that might be potential pharmacodynamic biomarkers in clinical trials.
Insights
Combining lapatinib and naproxen eliminated bladder tumors in a rat model, showing promise for treating basal cell carcinoma. This combination therapy may serve as a novel treatment strategy for bladder cancer.
Area of Science:
- Oncology
- Pharmacology
Background:
- Basal bladder cancer lacks effective targeted treatments.
- N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) in female F344 rats induces invasive bladder cancers, serving as a model for study.
Purpose of the Study:
- To evaluate the efficacy of EGFR inhibitors (erlotinib, lapatinib) and naproxen in treating bladder cancer in a rat model.
- To determine optimal dosing schedules (daily vs. weekly) for EGFR inhibitors.
- To investigate the combined effect of EGFR inhibitors and naproxen.
- To identify pharmacodynamic biomarkers through RNA analysis of treated tumors.
Main Methods:
- Female F344 rats were administered OH-BBN to induce bladder tumors.
- Tumor-bearing rats received daily or weekly doses of erlotinib or lapatinib, with or without daily naproxen.
- Tumor development and bladder weights were assessed.
- In a separate cohort, rats with palpable tumors were treated with EGFR inhibitors (erlotinib, lapatinib, gefitinib) or NO-naproxen for 5 days, followed by RNA analysis.
Main Results:
- Daily or weekly EGFR inhibitor administration and daily naproxen reduced tumor formation by up to 70%.
- The combination of daily lapatinib and naproxen resulted in a 100% reduction in tumor formation.
- EGFR inhibitors significantly downregulated cell proliferation and chromosome replication pathways.
- NO-naproxen modulated G protein receptor, oxygen homeostasis, and immune function pathways.
Conclusions:
- Combination therapy with lapatinib and naproxen demonstrated complete tumor eradication in the rat model.
- This combination holds potential for clinical use as an adjuvant or primary treatment for basal bladder tumors.
- Identified RNA pathways may serve as valuable pharmacodynamic biomarkers for future clinical trials.
