Takayama K, Reynolds P N, Adachi Y, Kaliberova L, Uchino J, Nakanishi Y, Curiel D T
Department of Medicine, Division of Human Gene Therapy, The University of Alabama at Birmingham, Birmingham, AL, USA.
Cancer Gene Ther. 2007 Jan;14(1):105-16. doi: 10.1038/sj.cgt.7700991. Epub 2006 Oct 6.
Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment.
由于肺癌的高发病率和高死亡率，晚期肺癌的治疗是当前医学面临的主要挑战之一。晚期肺癌对传统疗法具有抗性，预后极差。因此，需要新的治疗方法。肺肿瘤的形成依赖于血管生成，其中癌细胞产生的血管内皮生长因子（VEGF）起着关键作用。用可溶性VEGF受体中和VEGF可抑制肿瘤生长；然而，在肿瘤内血管网络形成后，这种疗法的抗癌效果会减弱。在本研究中，我们利用一种条件性复制缺陷型腺病毒（CRAd）将肿瘤中VEGF的表达转化为治疗优势，该腺病毒中E1的表达由人VEGF启动子控制。这种病毒在肺癌细胞中实现了良好的病毒复制水平，并在体外和体内诱导了显著的抗癌效果。作为进一步的增强，通过对病毒进行嗜性修饰以表达Ad3的纤突结构域来提高癌细胞杀伤效果，这提高了对癌细胞的感染性。这些基于VEGF启动子的CRAd对肺癌以外的多种癌细胞系也显示出显著的细胞杀伤作用。相反，VEGF启动子在正常组织中活性较低，CRAd对正常支气管上皮细胞没有损伤。由于通过VEGF信号传导的肿瘤相关血管生成在多种癌症中普遍存在，这些CRAd可能适用于广泛的肿瘤。我们得出结论，基于VEGF启动子的CRAd有潜力成为一种有效的癌症治疗策略。
