Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3

Ahonen, M., Ala-aho, R., Baker, A., George, S., Grenman, R., Saarialho-Kere, U. and Kahari, V. (2002) Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. Molecular Therapy, 5(6), pp. 705-715. (doi: 10.1006/mthe.2002.0606)

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Abstract

We have studied the effect of a newly identified tumor suppressor tissue inhibitor of metalloproteinases- 3 (TIMP-3) on the growth of human melanoma and squamous-cell carcinoma (SCC). Adenoviral delivery of the TIMP-3 gene to human melanoma (A2058) and SCC (UT-SCC-7) cells ex vivo inhibited tumorigenesis after subcutaneous (s.c.) injection of the infected cells into SCID/SCID mice. Three daily consecutive intratumoral injections of 1.4times109 plaque-forming units (pfu) of TIMP-3 adenovirus (RAdTIMP-3) inhibited the growth of preestablished melanoma and SCC xenografts in SCID/SCID mice, whereas growth of control virus-injected tumors was not affected. The antitumor effect of RAdTIMP-3 was obtained with in vivo adenoviral transduction efficiency of 8–%, and it was more potent than that of adenovirally delivered p53. Adenovirusmediated expression of TIMP-3 potently reduced gelatinolytic activity, increased the number of apoptotic cells, and inhibited vascularization of melanomas. Escalation of the adenoviral dose to three rounds of three daily consecutive injections with 1.4times109 pfu of RAdTIMP-3 every 6 days entirely inhibited growth of injected melanomas for 32 days. Mixing RAdTIMP-3-infected A2058 cells with uninfected cells in 1:1 ratio in culture resulted in death of all cells in 96 hours. Adenovirally delivered TIMP-3 was also expressed by A2058 cells in soluble form into the culture medium, where it exerted a cytotoxic effect on uninfected A2058 cell cultures after relocating to the cell layer. These results identify TIMP-3 as a novel type of secreted tumor suppressor, which has antiinvasive, antiangiogenic, and proapoptotic effects in vivo, and which displays a potent bystander effect validating further exploration of its applicability in human cancer gene therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew
Authors: Ahonen, M., Ala-aho, R., Baker, A., George, S., Grenman, R., Saarialho-Kere, U., and Kahari, V.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Molecular Therapy
Publisher:Nature Publishing Group
ISSN:1525-0016
ISSN (Online):1525-0024

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