Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice

Several lines of evidence now indicate that type 1 insulin-like growth fact or receptor (IGF1R) function may be particularly important in the pathogene sis of the pediatric cancer neuroblastoma. Modulating the expression of spe cific genes involved in neuroblastoma tumorigenesis could provide a much ne eded alternative treatment strategy for poor prognosis disease, We now repo rt construction of an antisense expression vector to the IGF1R that markedl y reduces cellular IGF1R Levels and inhibits the proliferation and clonogen icity of neuroblastoma cells in vitro but not that of IGF1R null cells. Thi s antitumor activity is associated with the induction of apoptotic cell dea th in transfected cells, as measured by annexin V staining and flow cytomet ry, Direct injection of this vector into established tumors growing in syng eneic mice results in a marked inhibition of tumor growth with complete and durable tumor regression in one-half of the animals, This effect appears t o he immunologically mediated in that vector injection of neuroblastoma tum ors growing in severe combined immunodeficiency mice results in only modest delay of tumor growth, Our results suggest that inhibition of IGF1R expres sion by direct intratumoral delivery of an antisense construct could provid e a novel therapeutic approach in the management of poor prognosis neurobla stoma.