Liu X, Turbyville T, Fritz A, Whitesell L
Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona, Tucson 85724, USA.
Cancer Res. 1998 Dec 1;58(23):5432-8.
Several lines of evidence now indicate that type 1 insulin-like growth factor receptor (IGF1R) function may be particularly important in the pathogenesis of the pediatric cancer neuroblastoma. Modulating the expression of specific genes involved in neuroblastoma tumorigenesis could provide a much needed alternative treatment strategy for poor prognosis disease. We now report construction of an antisense expression vector to the IGF1R that markedly reduces cellular IGF1R levels and inhibits the proliferation and clonogenicity of neuroblastoma cells in vitro but not that of IGF1R null cells. This antitumor activity is associated with the induction of apoptotic cell death in transfected cells, as measured by annexin V staining and flow cytometry. Direct injection of this vector into established tumors growing in syngeneic mice results in a marked inhibition of tumor growth with complete and durable tumor regression in one-half of the animals. This effect appears to be immunologically mediated in that vector injection of neuroblastoma tumors growing in severe combined immunodeficiency mice results in only modest delay of tumor growth. Our results suggest that inhibition of IGF1R expression by direct intratumoral delivery of an antisense construct could provide a novel therapeutic approach in the management of poor prognosis neuroblastoma.
目前有几条证据表明，1型胰岛素样生长因子受体（IGF1R）的功能在儿童癌症神经母细胞瘤的发病机制中可能尤为重要。调节神经母细胞瘤肿瘤发生过程中涉及的特定基因的表达，可为预后不良的疾病提供急需的替代治疗策略。我们现在报告构建了一种针对IGF1R的反义表达载体，该载体可显著降低细胞IGF1R水平，并在体外抑制神经母细胞瘤细胞的增殖和克隆形成能力，但对IGF1R缺失的细胞则无此作用。通过膜联蛋白V染色和流式细胞术检测，这种抗肿瘤活性与转染细胞中凋亡性细胞死亡的诱导有关。将该载体直接注射到同基因小鼠体内生长的已建立肿瘤中，可显著抑制肿瘤生长，一半的动物出现完全且持久的肿瘤消退。这种效应似乎是由免疫介导的，因为将载体注射到严重联合免疫缺陷小鼠体内生长的神经母细胞瘤肿瘤中，只会导致肿瘤生长的适度延迟。我们的结果表明，通过瘤内直接递送反义构建体抑制IGF1R表达，可为预后不良的神经母细胞瘤的治疗提供一种新的治疗方法。
