Réjiba Soukaina, Wack Séverine, Aprahamian Marc, Hajri Amor
Institut de Recherche sur les Cancers de l'Appareil Digestif (IRCAD), INSERM Unit 701, Tumor Biology and Gene Therapy Department, Strasbourg 67091, France.
Cancer Sci. 2007 Jul;98(7):1128-36. doi: 10.1111/j.1349-7006.2007.00506.x. Epub 2007 May 8.
Pancreatic adenocarcinoma remains a fatal disease characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. Gemcitabine is the current standard chemotherapy for advanced pancreatic cancer, but it is still far from optimal and novel therapeutic strategies are needed urgently. Mutations in the k-ras gene have been found in more than 90% of pancreatic cancers and are believed to play a key role in this malignancy. Thus, the goal of this study was to investigate the impact of k-ras oncogene silencing on pancreatic tumor growth. Additionally, we examined whether combining k-ras small interfering RNA (siRNA) with gemcitabine has therapeutic potential for pancreatic cancer. The treatment of tumor cell cultures with the corresponding k-ras siRNA resulted in a significant inhibition of k-ras endogenous expression and cell proliferation. In vivo, tumor xenografts were significantly reduced with k-ras siRNA(GAT) delivered by electroporation. Moreover, combined treatment with pSsik-ras(GAT) plus gemcitabine resulted in strong growth inhibition of orthotopic pancreatic tumors. Survival rate was significantly prolonged and the mean tumor volume was dramatically reduced in mice receiving the combined treatment compared with single agents. Collectively, these findings show that targeting mutant k-ras through specific siRNA might be effective for k-ras oncogene silencing and tumor growth inhibition. The improvement of gemcitabine-based chemotherapy suggests that this strategy might be used therapeutically against human pancreatic cancer to potentiate the effects of conventional therapy.
胰腺腺癌仍然是一种致命疾病，其特征为肿瘤进展迅速、转移潜力高且具有显著的化疗耐药性。吉西他滨是目前晚期胰腺癌的标准化疗药物，但仍远非最佳方案，迫切需要新的治疗策略。在超过90%的胰腺癌中发现了k-ras基因突变，并且认为该突变在这种恶性肿瘤中起关键作用。因此，本研究的目的是探讨k-ras癌基因沉默对胰腺肿瘤生长的影响。此外，我们还研究了将k-ras小干扰RNA（siRNA）与吉西他滨联合使用对胰腺癌是否具有治疗潜力。用相应的k-ras siRNA处理肿瘤细胞培养物可显著抑制k-ras内源性表达和细胞增殖。在体内，通过电穿孔递送的k-ras siRNA（GAT）可显著减少肿瘤异种移植。此外，pSsik-ras（GAT）与吉西他滨联合治疗可强烈抑制原位胰腺肿瘤的生长。与单一药物治疗相比，接受联合治疗的小鼠的生存率显著延长，平均肿瘤体积显著减小。总体而言，这些发现表明，通过特异性siRNA靶向突变的k-ras可能对k-ras癌基因沉默和肿瘤生长抑制有效。基于吉西他滨的化疗的改善表明，该策略可能用于治疗人类胰腺癌以增强传统疗法的效果。
