Gene Therapy of Breast Cancer: Studies of Selective Promoter/Enhancer-Modified Vectors to Deliver Suicide Genes

摘要

The overall goal of this project has been to develop gene therapy strategies for breast cancer by translation of studies derived from the DF3/MUC1 gene. Our studies have demonstrated that defective recombinant adenoviral vectors containing the DF3/MUC1 promoter (bps -725 to +31) can be used to selectively express the herpes simplex virus thymidine kinase (HSV-tk) gene (Ad. DF3-tk) in DF3/MUCl positive breast cancer cells in vitro and in animal model studies. On the basis of these findings, the replication defective adenoviral vectors containing the DF3/MUC1 promoter sequences have been used to selectively transduce contaminating breast cancer cells in human bone marrow and peripheral blood. Other studies have demonstrated that transduction of dendritic cells with replication defective adenoviral vectors expressing the DF3/MUC1 gene is effective for in vivo immunization against MUC1-positive tumor cells. These findings have provided the experimental basis for clinical trials of a novel vaccine against breast cancer. Finally, more recent work has involved the design of an adenoviral vector that is competent for replication in DF3/MUC1 1- positive, but not DF3/MUC1-negative, cells for the selective delivery of suicide genes to breast cancer cells in vivo.