Overexpression of RhoA or RhoC in breast cancer indicates a poor prognosis, due to increased tumor cell proliferation and invasion and tumor-dependent angiogenesis. Until now, the strategy of blockage of the Rho-signaling pathway has used either GGTI or HMG-CoA reductase inhibitors, but they are not specific to RhoA or RhoC inhibition. In this study, a new approach with anti-RhoA and anti-RhoC siRNAs was used to inhibit specifically RhoA or RhoC synthesis. Two transfections of either RhoA or RhoC siRNA (8.5 nM) into MDA-MB-231 human breast cancer cells or HMEC-1 endothelial cells induced extensive degradation of the target mRNA and led to a dramatic decrease in synthesis of the corresponding protein. In vitro, these siRNAs inhibited cell proliferation and invasion more effectively than conventional blockers of Rho cell signaling. Finally, in a nude mouse model, intratumoral injections of anti-RhoA siRNA (100 microl at 85 nM) every 3 days for 20 days almost totally inhibited the growth and angiogenesis of xenografted MDA-MB-231 tumors. One may infer from these observations that specific inhibition of the Rho-signaling pathway with siRNAs represents a promising approach for the treatment of aggressive breast cancers.

AdmATF is a recombinant adenovirus encoding a secreted within and at the vicinity of the injection site was also supversion of the amino-terminal fragment (ATF) of murine pressed, suggesting that AdmATF inhibited primary tumor urokinase (uPA). This defective adenovirus was used in growth by targeting angiogenesis. AdmATF also interfered three murine models to assess the antitumoral effects with tumor cell establishment at distant sites: (1) lung disassociated with local or systemic delivery of ATF, a broad semination of Lewis lung carcinoma cells was significantly cell invasion inhibitor that antagonizes uPA binding to its reduced following intratumoral injection at the primary site; cell surface receptor (uPAR). A single intratumoral injection and (2) systemic administration of AdmATF inhibited subof AdmATF into pre-established MDA-MB-231 human sequent liver metastasis in a LS174T human colon carcibreast xenografts grown in athymic mice, or into pre-estabnoma xenograft model. These data outline the potential of lished C57/BL6 syngeneic Lewis lung carcinoma resulted using a recombinant adenovirus directing the secretion of an in a specific arrest of tumor growth. Neovascularization antagonist of cell-associated uPA for cancer gene therapy.