Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-19-19 bladder cancer cell line in a mouse model
E Herrmann, A Tiemann, E Eltze, C Bolenz… - Journal of cancer …, 2009 - Springer
E Herrmann, A Tiemann, E Eltze, C Bolenz, C Bremer, T Persigehl, L Hertle, C Wülfing
Journal of cancer research and clinical oncology, 2009•SpringerPurpose The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ET A-and
ET B-receptor (ET AR and ET BR). In several tumor entities, the ET AR plays a significant
role as a drug target. In our study, we investigated whether inhibition of ET AR with
atrasentan leads to an antitumor effect in urinary bladder carcinoma as well. Materials and
methods Twenty nude mice with thymic aplasia were subcutaneously administered 2× 10 6
KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection …
ET B-receptor (ET AR and ET BR). In several tumor entities, the ET AR plays a significant
role as a drug target. In our study, we investigated whether inhibition of ET AR with
atrasentan leads to an antitumor effect in urinary bladder carcinoma as well. Materials and
methods Twenty nude mice with thymic aplasia were subcutaneously administered 2× 10 6
KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection …
Purpose
The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ETA- and ETB-receptor (ETA-R and ETB-R). In several tumor entities, the ETA-R plays a significant role as a drug target. In our study, we investigated whether inhibition of ETA-R with atrasentan leads to an antitumor effect in urinary bladder carcinoma as well.
Materials and methods
Twenty nude mice with thymic aplasia were subcutaneously administered 2 × 106 KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection, ten animals were treated with atrasentan (2.5 mg/kg BW intraperitoneally), and another ten animals were treated with placebo. During treatment, absolute tumor growth and relative growth rate over time were determined. After the end of treatment, the mitosis and necrosis rates, microvessel density, and receptor density in the tumor tissue were analyzed by immunohistochemistry. In addition, the expression intensities of ET-1, ETA-R, and ETB-R were evaluated semiquantitatively and compared between the groups.
Results
No significant differences between the active-treatment and placebo groups were detected, either with respect to absolute tumor growth (P = 0.333) or mitosis rate (P = 0.217). In the analysis of the necrosis rate and receptor density for ETA-R, a trend toward higher values in the active-treatment group (mean necrosis rate = 63.67%, receptor density: 1.417) than in the placebo group (mean necrosis rate = 46.25%, receptor density: 1.270) was found; however, neither difference was statistically significant (P = 0.08 and 0.219, respectively).
Conclusions
ETA-R blockade with atrasentan in a bladder cancer xenograft model shows no significant antitumor effect.
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