Recombinant adenovirus AdTIMP-2 inhibits tumor growth, angiogenesis and metastasis, and prolongs survival in mice

H. Li, F.Lidenmeyer, C. Grenet, P. Opolon, S. Menashi, C. Soria, P. Yeh, M. Perricaudet and H. Lu

CNRS UMR 1582, Institut Gustave Roussy, 39, Rue C. Desmoulins Villejuif 94805, France

Since tumor invasion, angiogenesis, and metatstasis are all invasive processes, targeting cell invasion to achieve an accumulative benefit in cancer therapy represents a most promising strategy. Cell invasion involves basically matrix metalloproteinase (MMP)-mediated matrix proteolysis, which is counterbalanced in vivo by the natural tissue inhibitors of MMPs (TIMPs). Among TIMPs, TIMP-2 has been shown to abolishes the hydrolytic activity of all activated members of the metalloproteinase family and in particular that of MT1-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis. Since MMPs have been implicated in both cancer progression and angiogenesis, we generated a recombinant adenovirus to deliver human TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 inhibited the invasion of both tumor and endothelial cells without affecting cell proliferation. Its in vivo efficiency has been evaluated in murine lung carcinoma LLC, and colon cancer C51 in syngeneic mice as well as in human breast cancer MDA-MB-231 in athymic mice. Preinfection of tumor cells by AdTIMP-2 resulted in an inhibition of tumor establishment in more than 50% of mice in LLC and C51 models and in 100% mice in the MDA-MB-231 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 angiogenesis index by 25-27%. Lung metastasis of LLC tumor was inhibited by >90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged survival in LLC and C51 metastatic tumor models. These data demonstrate the potential of adenovirus-mediated TIMP-2 therapy in cancer treatment.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 2.