A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice

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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.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.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.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.language.iso en es
dc.publisher American Association for Cancer Research es
dc.rights openAccess
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
dc.description.peerreviewed Peer reviewed es
dc.relation.publisherversion http://clincancerres.aacrjournals.org/content/15/23/7256.full es
dc.rights.text © American Association for Cancer Research es

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