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Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma

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Author: Lamfers, M.L.M. · Gianni, D. · Tung, C.H. · Idema, S. · Schagen, F.H.E. · Carette, J.E. · Quax, P.H.A. · Beusechem, V.W. van · Top, W.P. van der · Dirven, C.M.F. · Chiocca, E.A. · Gerritsen, W.R.
Institution: TNO Kwaliteit van Leven
Source:Cancer Research, 20, 65, 9398-9405
Identifier: 238761
doi: doi:10.1158/0008-5472.CAN-04-4264
Keywords: Biomedical Research · oncolytic adenovirus · oncolytic virus · tissue inhibitor of metalloproteinase 3 · Adenovirus · animal experiment · animal model · animal tissue · antineoplastic activity · article · cancer cell culture · cancer model · cancer survival · cell proliferation · cell strain HEK293 · controlled study · culture medium · drug efficacy · enzyme activity · enzyme inhibition · female · gene deletion · gene expression · gene insertion · gene transfer · glioblastoma · glioma cell · human · human cell · mouse · nonhuman · priority journal · protein expression · survival time · transgene · tumor xenograft · Adenoviridae · Animals · Cell Growth Processes · Cell Line, Tumor · Gene Transfer Techniques · Glioma · Humans · Matrix Metalloproteinase 2 · Mice · Mice, Nude · Tissue Inhibitor of Metalloproteinase-3 · Virus Replication · Xenograft Model Antitumor Assays


Oncolytic adenoviruses exhibiting tumor-selective replication are promising anticancer agents. Insertion and expression of a transgene encoding tissue inhibitor of metalloproteinase-3 (TIMP-3), which has been reported to inhibit angiogenesis and tumor cell infiltration and induce apoptosis, may improve the antitumor activity of these agents. To assess the effects of TIMP-3 gene transfer to glioma cells, a replication-defective adenovirus encoding TIMP-3 (Ad.TIMP-3) was employed. Ad.TIMP-3 infection of a panel of glioma cell cultures decreased the proliferative capacity of these cells and induced morphologic changes characteristic for apoptosis. Next, a conditionally replicating adenovirus encoding TIMP-3 was constructed by inserting the TIMP-3 expression cassette into the E3 region of the adenoviral backbone containing a 24-bp deletion in E1A. This novel oncolytic adenovirus, AdΔ24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdΔ24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdΔ24TIMP-3 was shown in s.c. glioma xenografts. The functional activity of TIMP-3 was imaged noninvasively using a near-IR fluorescent MMP-2-activated probe. Tumoral MMP-2 activity was significantly reduced by 58% in the AdΔ24TIMP-3-treated tumors 24 hours after infection. A study into the therapeutic effects of combined oncolytic and antiproteolytic therapy was done in both a s.c. and an intracranial model for malignant glioma. Treatment of s.c. (U-87MG) or intracranial (U-87δEGFR) tumors with AdΔ24TIMP-3 and AdΔ24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdΔ24 did not significantly affect the antitumor efficacy of this oncolytic agent. ©2005 American Association for Cancer Research. Chemicals / CAS: tissue inhibitor of metalloproteinase 3, 145809-21-8, 164781-40-2; Matrix Metalloproteinase 2, EC; Tissue Inhibitor of Metalloproteinase-3