AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongssurvival in mice

TIMP-2 is a natural matrix metalloproteinase (MMP) inhibitor that prevents the degradation of extracellular matrix proteins. It abolishes the hydrolyt ic activity of all activated members of the metalloproteinase family and in particular that of MTI-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis, Since MMPs have been implicated in both cancer progress ion and angiogenesis, we generated a recombinant adenovirus to deliver huma n TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 in hibited the invasion of both tumor and endothelial cells without affecting cell proliferation, Its in vivo efficiency has been evaluated in murine lun g cancer LLC, and colon cancer C51 in syngeneic mice as well as in human br east cancer MDA-MB231 in athymic mice. Preinfection of tumor cells by AdTIM P-2 resulted in an inhibition of tumor establishment in more than 50% of mi ce In LLC and C51 models and in 100% mice in the MDA-MB231 model. A single local injection of AdTIMP-2 into preestablished tumors of these three types significantly reduced tumor growth rates by 60-80% and tumor-associated an giogenesis index by 25-75%. Lung metastasis of LLC tumor was inhibited by > 90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged su rvival in all the cancer models tested. These data demonstrate the potentia l of adenovirus-mediated TIMP-2 therapy in cancer treatment.