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Updated: Jun 24, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
In vivo studies on the availability and toxicity of antisense oligonucleotides in bladder cancer
Caroline E Blietz1, Beate Thode, Martin Hauses
1Department of Urology, University of Lübeck, Lübeck, Germany.
Background:
The urinary bladder is an ideal organ for topical treatment. A substantial number of bladder cancer patients are resistant to conventional intravesical therapy. In search of new agents, antisense oligonucleotides (AS-ON) may be interesting candidates. The availability and toxicity as well as the effectivity of AS-ON after intravesical instillation in different rodent models were examined.
Materials And Methods:
Acute toxicity of AS-ON was tested by intravenous application (215-1,000 mg/kg body weight (bw)) in NMRI mice (n=30). The uptake and distribution of isotope-labelled AS-ON in bladder tissue was determined in Sprague Dawley rats (n=12) by radioactivity after intravesical application (2.5 mg/kg bw 3H-labelled AS-ON). Additionally, uptake and effectivity studies of AS-ON in tumors were performed in MB-49 bladder cancer-bearing C57/B16 mice (n=6) by immunohistochemistry and fluorescence microscopy.
Results:
No systematic side-effects were noticed after intravenous application of physiological doses of AS-ON in NMRI mice. The mortality rate was 20% at the highest dose of 1,000 mg/kg bw. The highest AS-ON availability after intravesical application in rats was noticed in the bladder wall (12.3 microg/g), while the systemic concentration was low (1.1 microg/g). In fluorescence microscopy analysis, AS-ON were detected in the outer cells of the bladder wall and around vessels. AS-ON accumulated in the cytoplasm and in the nuclei. Immunohistochemical analysis demonstrated a reduction of the Ki-67 positivity after treatment with AS-ON (43%) compared to the untreated controls (58%).
Conclusion:
These preclinical experiments have shown that intravesical antisense oligonucleotides are safe and accumulate in the bladder and in bladder tumors, whereas systemic concentrations remain low. These data are the basis of a first clinical phase I study with intravesical instillation of Ki-67 antisense oligonucleotides.
Insights
Antisense oligonucleotides (AS-ON) show promise for topical bladder cancer treatment. These agents are safe, accumulate in bladder tumors after intravesical instillation, and have low systemic exposure, supporting clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Bladder cancer often exhibits resistance to conventional intravesical therapies.
- Antisense oligonucleotides (AS-ON) are explored as novel agents for topical bladder treatment.
- Preclinical evaluation of AS-ON for bladder cancer is necessary due to treatment resistance.
Purpose of the Study:
- To assess the safety, availability, and efficacy of antisense oligonucleotides (AS-ON) following intravesical instillation in rodent models.
- To determine the distribution and accumulation of AS-ON within bladder tissue and tumors.
- To evaluate the therapeutic potential of AS-ON in preclinical bladder cancer models.
Main Methods:
- Acute toxicity of AS-ON was evaluated in NMRI mice via intravenous administration.
- Uptake and distribution of 3H-labelled AS-ON in Sprague Dawley rats were measured after intravesical instillation.
- AS-ON efficacy in MB-49 bladder tumors was assessed using immunohistochemistry and fluorescence microscopy in C57/B16 mice.
Main Results:
- Intravenous AS-ON showed no systematic side effects at physiological doses; 20% mortality at 1,000 mg/kg.
- Intravesical AS-ON achieved high bladder wall availability (12.3 microg/g) with low systemic concentrations (1.1 microg/g) in rats.
- AS-ON accumulated in bladder tumor cells and reduced Ki-67 proliferation marker (43% vs. 58% in controls).
Conclusions:
- Intravesical AS-ON demonstrate favorable safety and pharmacokinetic profiles for bladder cancer treatment.
- AS-ON effectively accumulate in bladder tumors, suggesting topical efficacy.
- These findings support the initiation of a Phase I clinical trial for intravesical Ki-67 AS-ON therapy.
