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

Martine L. M. Lamfers; Davide Gianni; Ching-Hsuan Tung; Sander Idema; Frederik H. E. Schagen; Jan E. Carette; Paul H. A. Quax; Victor W. van Beusechem; W. Peter Vandertop; Clemens M. F. Dirven; E. Antonio Chiocca; Winald R. Gerritsen

doi:https://doi.org/10.1158/0008-5472.CAN-04-4264

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

Martine L. M. Lamfers, Davide Gianni, Ching-Hsuan Tung, Sander Idema, Frederik H. E. Schagen, Jan E. Carette, Paul H. A. Quax, Victor W. van Beusechem, W. Peter Vandertop, Clemens M. F. Dirven, E. Antonio Chiocca, Winald R. Gerritsen

Research output: Contribution to journal › Article › Academic › peer-review

48 Citations (Scopus)

Abstract

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, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-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 AdDelta24TIMP-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-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent

Original language	English
Pages (from-to)	9398-9405
Number of pages	8
Journal	Cancer research
Volume	65
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-04-4264
Publication status	Published - 15 Oct 2005

Keywords

Adenoviridae/genetics
Animals
Cell Growth Processes/genetics
Cell Line, Tumor
Gene Transfer Techniques
Glioma/enzymology
Humans
Matrix Metalloproteinase 2/metabolism
Matrix Metalloproteinase Inhibitors
Mice
Mice, Nude
Tissue Inhibitor of Metalloproteinase-3/biosynthesis
Virus Replication
Xenograft Model Antitumor Assays

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https://doi.org/10.1158/0008-5472.CAN-04-4264

Cite this

Lamfers, M. L. M., Gianni, D., Tung, C.-H., Idema, S., Schagen, F. H. E., Carette, J. E., Quax, P. H. A., van Beusechem, V. W., Vandertop, W. P., Dirven, C. M. F., Chiocca, E. A., & Gerritsen, W. R. (2005). Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma. Cancer research, 65(20), 9398-9405. https://doi.org/10.1158/0008-5472.CAN-04-4264

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

abstract = "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, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-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 AdDelta24TIMP-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-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent",

keywords = "Adenoviridae/genetics, Animals, Cell Growth Processes/genetics, Cell Line, Tumor, Gene Transfer Techniques, Glioma/enzymology, Humans, Matrix Metalloproteinase 2/metabolism, Matrix Metalloproteinase Inhibitors, Mice, Mice, Nude, Tissue Inhibitor of Metalloproteinase-3/biosynthesis, Virus Replication, Xenograft Model Antitumor Assays",

author = "Lamfers, {Martine L. M.} and Davide Gianni and Ching-Hsuan Tung and Sander Idema and Schagen, {Frederik H. E.} and Carette, {Jan E.} and Quax, {Paul H. A.} and {van Beusechem}, {Victor W.} and Vandertop, {W. Peter} and Dirven, {Clemens M. F.} and Chiocca, {E. Antonio} and Gerritsen, {Winald R.}",

year = "2005",

month = oct,

day = "15",

doi = "https://doi.org/10.1158/0008-5472.CAN-04-4264",

language = "English",

volume = "65",

pages = "9398--9405",

journal = "Cancer research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "20",

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Lamfers, MLM, Gianni, D, Tung, C-H, Idema, S, Schagen, FHE, Carette, JE, Quax, PHA, van Beusechem, VW , Vandertop, WP, Dirven, CMF, Chiocca, EA & Gerritsen, WR 2005, 'Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma', Cancer research, vol. 65, no. 20, pp. 9398-9405. https://doi.org/10.1158/0008-5472.CAN-04-4264

Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma. / Lamfers, Martine L. M.; Gianni, Davide; Tung, Ching-Hsuan et al.
In: Cancer research, Vol. 65, No. 20, 15.10.2005, p. 9398-9405.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma

AU - Lamfers, Martine L. M.

AU - Gianni, Davide

AU - Tung, Ching-Hsuan

AU - Idema, Sander

AU - Schagen, Frederik H. E.

AU - Carette, Jan E.

AU - Quax, Paul H. A.

AU - van Beusechem, Victor W.

AU - Vandertop, W. Peter

AU - Dirven, Clemens M. F.

AU - Chiocca, E. Antonio

AU - Gerritsen, Winald R.

PY - 2005/10/15

Y1 - 2005/10/15

N2 - 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, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-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 AdDelta24TIMP-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-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent

AB - 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, AdDelta24TIMP-3, showed enhanced oncolytic activity on a panel of primary cell cultures and two glioma cell lines compared with the control oncolytic virus AdDelta24Luc. In vivo inhibition of matrix metalloproteinase (MMP) activity by AdDelta24TIMP-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 AdDelta24TIMP-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-87deltaEGFR) tumors with AdDelta24TIMP-3 and AdDelta24Luc both significantly inhibited tumor growth and prolonged survival compared with PBS-treated controls. However, expression of TIMP-3 in the context of AdDelta24 did not significantly affect the antitumor efficacy of this oncolytic agent

KW - Adenoviridae/genetics

KW - Animals

KW - Cell Growth Processes/genetics

KW - Cell Line, Tumor

KW - Gene Transfer Techniques

KW - Glioma/enzymology

KW - Humans

KW - Matrix Metalloproteinase 2/metabolism

KW - Matrix Metalloproteinase Inhibitors

KW - Mice

KW - Mice, Nude

KW - Tissue Inhibitor of Metalloproteinase-3/biosynthesis

KW - Virus Replication

KW - Xenograft Model Antitumor Assays

U2 - https://doi.org/10.1158/0008-5472.CAN-04-4264

DO - https://doi.org/10.1158/0008-5472.CAN-04-4264

M3 - Article

C2 - 16230403

SN - 0008-5472

VL - 65

SP - 9398

EP - 9405

JO - Cancer research

JF - Cancer research

IS - 20

ER -