File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1002/jgm.201
- Scopus: eid_2-s2.0-0035407547
- PMID: 11529668
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: Systemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo
Title | Systemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo |
---|---|
Authors | |
Keywords | Gene therapy IFN-γ IL-12 toxicity |
Issue Date | 2001 |
Citation | Journal of Gene Medicine, 2001, v. 3 n. 4, p. 384-393 How to Cite? |
Abstract | Background: IL-12 is a potent antitumor cytokine for cancer gene therapy. Previously, we demonstrated that single systemic administration of naked DNA (encoding IL-12) could serve as a good model for in vivo evaluation of the antitumor effect of a candidate gene (unpublished data). In the present study, we propose that this gene delivery method could be a very useful model for in vivo evaluation of the toxicity of a given therapeutic gene (using IL-12 as an example). By comparing the toxicities and the effects of initial IL-12 administration on subsequent transgene expression, both IL-12 gene delivery and recombinant murine IL-12 protein (rmIL-12) administration showed similar toxicity profiles. Methods: Naked DNA encoding murine IL-12 (mIL-12) was delivered into mice by systemic administration. Toxicity profiles of mice treated with DNA or rmIL-12 were compared. Results: Systemic administration of naked DNA encoding mIL-12 resulted in very similar toxicity as rmIL-12 with respect to liver enzyme, hematological and immunological profiles. Repeated injection of mIL-12 gene did not recover a high level of mIL-12 production as the first injection. Moreover, initial mIL-12 administration resulted in inhibition of subsequent reporter gene expression with both viral and non-viral promoters (CMV, human α-antitrypsin or chicken β-actin promoter). This transgene inhibition effect was entirely mediated by IFN-γ as the transgene expression was fully recovered in IFN-y knockout mice. Conclusions: Systemic IL-12 therapy, with either a protein or gene therapy approach, resulted in comparable liver and systemic toxicities. Refractoriness of mIL-12 production by subsequent administration of mIL-12 gene was observed. The transgene attenuation effect of IL-12 pre-dosing (either by IL-12 or rmIL-12), mediated by IFN-γ, provided important insights for the design of IL-12 combination gene therapy and the improvement of gene vectors for IL-12 therapy. The present results show that simple injection of naked DNA could serve as a good model for in vivo evaluation of the toxicity of a candidate therapeutic gene. Copyright © 2001 John Wiley & Sons, Ltd. |
Persistent Identifier | http://hdl.handle.net/10722/194122 |
ISSN | 2023 Impact Factor: 3.2 2023 SCImago Journal Rankings: 0.679 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lui, VWY | - |
dc.contributor.author | Falo Jr, LD | - |
dc.contributor.author | Huang, L | - |
dc.date.accessioned | 2014-01-30T03:32:11Z | - |
dc.date.available | 2014-01-30T03:32:11Z | - |
dc.date.issued | 2001 | - |
dc.identifier.citation | Journal of Gene Medicine, 2001, v. 3 n. 4, p. 384-393 | - |
dc.identifier.issn | 1099-498X | - |
dc.identifier.uri | http://hdl.handle.net/10722/194122 | - |
dc.description.abstract | Background: IL-12 is a potent antitumor cytokine for cancer gene therapy. Previously, we demonstrated that single systemic administration of naked DNA (encoding IL-12) could serve as a good model for in vivo evaluation of the antitumor effect of a candidate gene (unpublished data). In the present study, we propose that this gene delivery method could be a very useful model for in vivo evaluation of the toxicity of a given therapeutic gene (using IL-12 as an example). By comparing the toxicities and the effects of initial IL-12 administration on subsequent transgene expression, both IL-12 gene delivery and recombinant murine IL-12 protein (rmIL-12) administration showed similar toxicity profiles. Methods: Naked DNA encoding murine IL-12 (mIL-12) was delivered into mice by systemic administration. Toxicity profiles of mice treated with DNA or rmIL-12 were compared. Results: Systemic administration of naked DNA encoding mIL-12 resulted in very similar toxicity as rmIL-12 with respect to liver enzyme, hematological and immunological profiles. Repeated injection of mIL-12 gene did not recover a high level of mIL-12 production as the first injection. Moreover, initial mIL-12 administration resulted in inhibition of subsequent reporter gene expression with both viral and non-viral promoters (CMV, human α-antitrypsin or chicken β-actin promoter). This transgene inhibition effect was entirely mediated by IFN-γ as the transgene expression was fully recovered in IFN-y knockout mice. Conclusions: Systemic IL-12 therapy, with either a protein or gene therapy approach, resulted in comparable liver and systemic toxicities. Refractoriness of mIL-12 production by subsequent administration of mIL-12 gene was observed. The transgene attenuation effect of IL-12 pre-dosing (either by IL-12 or rmIL-12), mediated by IFN-γ, provided important insights for the design of IL-12 combination gene therapy and the improvement of gene vectors for IL-12 therapy. The present results show that simple injection of naked DNA could serve as a good model for in vivo evaluation of the toxicity of a candidate therapeutic gene. Copyright © 2001 John Wiley & Sons, Ltd. | - |
dc.language | eng | - |
dc.relation.ispartof | Journal of Gene Medicine | - |
dc.subject | Gene therapy | - |
dc.subject | IFN-γ | - |
dc.subject | IL-12 toxicity | - |
dc.title | Systemic production of IL-12 by naked DNA mediated gene transfer: Toxicity and attenuation of transgene expression in vivo | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1002/jgm.201 | - |
dc.identifier.pmid | 11529668 | - |
dc.identifier.scopus | eid_2-s2.0-0035407547 | - |
dc.identifier.volume | 3 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 384 | - |
dc.identifier.epage | 393 | - |
dc.identifier.issnl | 1099-498X | - |