Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. In this study, we investigated the effects of recombinant adeno-associated virus (AAV)-mediated delivery of K5 in mouse models of human ovarian cancer. A single intramuscular injection of AAV-K5 resulted in sustained expression of K5 reaching a maximum serum level of 800 ng ml-1. Gene therapy inhibited both vascular endothelial growth factor (VEGF)-induced and tumor cell-induced angiogenesis in matrigel plug assays. Furthermore, a single injection of AAV-K5 significantly inhibited both subcutaneous and intraperitoneal growth of human ovarian cancer cells. Immunofluorescence studies of residual tumors surgically resected from the treated animals showed reduced tumor burden, which correlated with the inhibition of tumor neovascularization. In addition, AAV-K5 gene therapy differentially affected the nascent vessels more than mature vasculature and induced apoptotic death of tumor cells. These data show that AAV-K5 can be effectively used to inhibit ovarian cancer.
Bibliographical noteFunding Information:
We thank John Oja, Jerry Sedgewick, Dr Ruud Dings, Lynn Weber, Julia Nguyen, Dr Sabita Roy, and Dr Rakesh Kumar for their help and support. This work was supported in part by a grant from the National Institutes of Health CA114340 and Sparboe Endowment for Women’s Cancer Research (SR).
Copyright 2019 Elsevier B.V., All rights reserved.
- Adeno-associated virus
- Kringle 5
- Ovarian cancer