Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-|[beta]| gene therapy

摘要

We have previously reported that adenoviral vector-mediated interferon (IFN)- gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN- (AdmIFN-), but not AdE/1 (a control adenoviral vector), produced approximately 60ng/105 cells/24h of IFN-. The tumorigenicity of AdmIFN--transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 109PFU (plaque-forming unit) of AdmIFN- inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN- therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN- in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN- therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN- gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN- antitumoral effects in vivo.