A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice
| dc.contributor.author | Malvicini, Mariana | |
| dc.contributor.author | Rizzo, Miguel | |
| dc.contributor.author | Alaniz, Laura | |
| dc.contributor.author | Piñero, Federico | |
| dc.contributor.author | García, Mariana | |
| dc.contributor.author | Atorrasagasti, Catalina | |
| dc.contributor.author | Aquino, Jorge B. | |
| dc.contributor.author | Rozados, Viviana R. | |
| dc.contributor.author | Scharovsky, O. Graciela | |
| dc.contributor.author | Matar, Pablo | |
| dc.contributor.author | Mazzolini, Guillermo | |
| dc.date.accessioned | 2012-08-24T17:37:01Z | |
| dc.date.available | 2012-08-24T17:37:01Z | |
| dc.date.issued | 2009-11 | |
| dc.description.abstract | PURPOSE: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. EXPERIMENTAL DESIGN: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. RESULTS: The combined therapy induced a complete tumor regression in >50% of mice in a synergistic fashion, and it significantly prolonged their survival. This strategy was superior to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+ regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-gamma-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10 levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide with AdIL-12 allows the generation of good antitumoral responses, thus avoiding undesired side effects of both agents. CONCLUSIONS: Our data strongly support the use of a combination of cyclophosphamide and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma. | es |
| dc.description.peerreviewed | Peer reviewed | es |
| dc.description.sponsorship | Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) grant PICT-2005/34788 (P. Matar, V. Rozados, O.G. Scharovsky and G. Mazzolini); PICTO-CRUP 2005/31179 (G. Mazzolini); AECID 2008 D/022066/08 (G. Mazzolini). LA work is supported in part by Mizutani Foundation. C. Atorrasagasti and M. Malvicini are fellows from ANPCyT. | es |
| dc.format | application/pdf | |
| dc.identifier.citation | Malvicini, M., Rizzo, M., Alaniz, L., Pinero, F., Garcia, M., Atorrasagasti, C., Aquino, J. B., ... Mazzolini, G. (November 30, 2009). A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice. Clinical Cancer Research, 15, 23, 7256-7265 | es |
| dc.identifier.issn | 1078-0432 | |
| dc.identifier.uri | http://hdl.handle.net/2133/2009 | |
| dc.language.iso | en | es |
| dc.publisher | American Association for Cancer Research | es |
| dc.relation.publisherversion | http://clincancerres.aacrjournals.org/content/15/23/7256.full | es |
| dc.rights | openAccess | |
| dc.rights.text | © American Association for Cancer Research | es |
| dc.subject | Combined immunotherapy | es |
| dc.subject | Cyclophosphamide gene therapy | es |
| dc.subject | Interleukin-12 | es |
| dc.subject | Colorectal carcinoma | es |
| dc.title | A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice | es |
| dc.type | article | |
| dc.type | artículo | |
| dc.type | publishedVersion |