In vivo studies on the availability and toxicity of antisense oligonucleotides in bladder cancer.

Abstract

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.

• Authors: Caroline E Blietz, Beate Thode, Martin Hauses, Ralph Pries, Alexander J Meyer, Christian Doehn, Dieter Jocham, Ingo Kausch
• Journal: In vivo (Athens, Greece) (In Vivo) 2009 Jan-Feb Vol. 23 Issue 1 Pg. 13-9 ISSN: 0258-851X [Print] Greece
• PMID: 19368119 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Ki-67 Antigen
• Oligonucleotides, Antisense

Topics

• Administration, Intravesical
• Animals
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Injections, Intravenous
• Ki-67 Antigen (genetics, metabolism)
• Longevity (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Oligonucleotides, Antisense (pharmacokinetics, toxicity)
• Rats
• Rats, Sprague-Dawley
• Toxicity Tests, Acute
• Urinary Bladder (drug effects, metabolism)
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology)