Kunze Doreen, Wuttig Daniela, Kausch Ingo, Blietz Caroline, Blumhoff Lena, Burmeister Yvonne, Kraemer Kai, Fuessel Susanne, Toma Marieta, Schwenzer Bernd, Meye Axel, Grimm Marc-Oliver, Hakenberg Oliver W, Jocham Dieter, Wirth Manfred P
Department of Urology, Faculty of Medicine, Technical University of Dresden, 01307 Dresden, Germany.
Int J Oncol. 2008 May;32(5):1049-56.
Since cancer cells are characterised by multiple genetic alterations the single inhibition of one tumour- associated gene might not be sufficient as a therapeutic strategy. We examined the effects of a combined inhibition of survivin, human telomerase reverse transcriptase (hTERT) and vascular endothelial growth factor (VEGF) with antisense oligodeoxynucleotides (AS-ODNs) and small interfering RNAs (siRNAs) in EJ28 and 5637 bladder cancer (BCa) cells. Following verification of the uptake of intraperitoneally applied fluorescence-labelled AS-ODNs and siRNAs in subcutaneous BCa xenografts, the target-directed constructs were tested as single agents in SCID mice bearing subcutaneous EJ28. Simultaneous inhibition of two of the selected transcripts significantly enhanced cell viability reduction compared to the controls consisting of a target directed construct and an appropriate control construct without any homology to the human genome. The uptake of both antisense inhibitor types in the subcutaneous BCa was achieved even without a carrier. In vivo studies with 9 consecutive intraperitoneal injections with 20 mg/kg AS-ODNs or 4.6 mg/kg siRNAs revealed the biocompatibility of both antisense inhibitor types and showed anti-tumoural activity of the AS-ODNs used.
由于癌细胞具有多种基因改变的特征，单一抑制一种肿瘤相关基因作为治疗策略可能并不足够。我们研究了用反义寡脱氧核苷酸（AS-ODNs）和小干扰RNA（siRNAs）联合抑制生存素、人端粒酶逆转录酶（hTERT）和血管内皮生长因子（VEGF）对EJ28和5637膀胱癌细胞（BCa）的影响。在皮下BCa异种移植瘤中验证腹腔注射荧光标记的AS-ODNs和siRNAs的摄取后，将靶向构建体作为单一药物在携带皮下EJ28的SCID小鼠中进行测试。与由靶向构建体和与人基因组无任何同源性的适当对照构建体组成的对照组相比，同时抑制两种选定转录本显著增强了细胞活力降低。即使没有载体，两种反义抑制剂类型在皮下BCa中也能实现摄取。对20mg/kg AS-ODNs或4.6mg/kg siRNAs进行9次连续腹腔注射的体内研究揭示了两种反义抑制剂类型的生物相容性，并显示了所用AS-ODNs的抗肿瘤活性。
