Effects of survivin antagonists of growth of established tumors and B7-1 immunogene therapy

Kanwar, Jagat R., Shen,Wei-Ping, Kanwar, Rupinder K., Berg, Randal W. and Krissansen, Geoffrey W. 2001, Effects of survivin antagonists of growth of established tumors and B7-1 immunogene therapy, Journal of the National Cancer Institute, vol. 93, no. 20, pp. 1541-1552, doi: 10.1093/jnci/93.20.1541.

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Title Effects of survivin antagonists of growth of established tumors and B7-1 immunogene therapy
Author(s) Kanwar, Jagat R.ORCID iD for Kanwar, Jagat R. orcid.org/0000-0003-3728-9568
Kanwar, Rupinder K.
Berg, Randal W.
Krissansen, Geoffrey W.
Journal name Journal of the National Cancer Institute
Volume number 93
Issue number 20
Start page 1541
End page 1552
Total pages 12
Publisher Oxford University Press
Place of publication Oxford, England
Publication date 2001-10-17
ISSN 0027-8874
Summary Background: Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is detectable in most types of cancer, and its presence is associated with a poor prognosis. We determined the effects of gene-based therapies that inhibit survivin function in a mouse tumor model. Methods: Using five to six mice per treatment group, we injected tumors derived from mouse EL-4 thymic lymphoma cells with plasmids encoding antisense survivin, a dominant-negative mutant survivin, and the T-cell costimulator B7-1. Expression of endogenous survivin and the proteins encoded by the injected plasmids were examined by immunohistochemical staining of tumor sections and by western blot and flow cytometry analyses of isolated tumor cells. Tumor growth, the generation of antitumor cytotoxic T-lymphocyte (CTL) activity, apoptosis, and the contribution of leukocyte subsets to antitumor activity were measured. All statistical tests were two-sided. Results: Large (1.0-cm diameter) tumors had approximately 10-fold more survivin than small (0.2-cm diameter) tumors. At 28 days after injection, antisense and dominant-negative mutant survivin plasmids statistically significantly inhibited the growth of both small (P = .006 and P = .0018, respectively) and large (P<.001 for both plasmids) EL-4 tumors compared with tumors injected with empty plasmid. The growth of large tumors was further inhibited by intratumoral injection with antisense survivin and B7-1 (P = .004); thus, inhibition of survivin expression renders large tumors susceptible to B7-1-mediated immunotherapy. Mice whose tumors were completely eradicated by injection of B7-1 remained tumor free for 26 days after re-injection with EL-4 cells (when the experiment ended). Compared with tumors injected with empty plasmid, tumors injected with survivin-based plasmids had increased apoptosis, and animals bearing such tumors generated more antitumor CTLs. Conclusion: Intratumoral injection of plasmids that block survivin expression and stimulate the generation of tumor-specific CTLs may be beneficial for the treatment of large lymphomas.
Language eng
DOI 10.1093/jnci/93.20.1541
Field of Research 111204 Cancer Therapy (excl Chemotherapy and Radiation Therapy)
110706 Immunogenetics (incl Genetic Immunology)
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2001, Oxford University Press
Persistent URL http://hdl.handle.net/10536/DRO/DU:30026295

Document type: Journal Article
Collection: Institute of Biotechnology
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Created: Tue, 30 Mar 2010, 12:53:09 EST by Rupinder Kanwar

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