Artikel
Attenuation of tumor growth and antiangiogenic effects of the nitric oxide donor JS-K in U87 gliomas in vivo
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Veröffentlicht: | 20. Mai 2009 |
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Gliederung
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Objective: The diazeniumdiolate JS-K generates nitric oxide (NO) after enzymatic activation by GST and has potent growth-inhibitory effects in U87 glioma cells and induced chemosensitization to imatinib (Glivec®) in vitro. The objective was to evaluate this approach in vivo.
Methods: Nude rats were inoculated with 106 U87 cells into both flanks. Treatment with JS-K (O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazine-1-yl]diazene-1-ium-1,2-diolate; 6mg/kg/d s.c.), imatinib (50mg/kg/d i.p.) or a combination was administered daily over 7 days when tumors reached a volume of 800-900 mm3. Tumor size was measured three times per week using calipers over a study period of up to 42 days, and tumor volume (formula: l x w2/2), tumor volume quadrupling time and survival/reaching of endpoint criteria (tumor volume=50.000mm3) were analyzed using ANOVA and survival analysis. Tumor specimens were analyzed histologically und immunohistochemically.
Results: Treatment with s.c. JS-K was safe and induced a significant attenuation of tumor growth (p=0.009). Tumor volume quadrupling time was doubled from 8 to 16 days in the JS-K group. Although survival in the JS-K group was longer, it did not reach statistical significance. No chemosensitizing effect was observed as the combination of JS-K + imatinib and imatinib alone were not effective. Histological workup revealed tumor necrosis and a reduction in tumor vasculature suggesting an antiangiogenic effect of JS-K.
Conclusions: This is the first report that the NO donor JS-K has antiproliferative and antiangiogenic effects in a U87 flank tumor model in vivo. Current projects study the efficacy in an intracranial model and the effects on tumor vasculature.